1. Field of the Invention
The present invention discloses a material comprising an assemblage of particles releasing active substances, such as, but not limited to, pharmaceuticals, over a prolonged period of time following a zero order kinetic.
2. Background
The sustained-release of active substances (AS) over long time-scales is a desirable characteristic in many areas such as crop science, medicine, cosmetics, etc. The term “active substance” used in this context denotes any substance that fulfils a specified function. The active substance can be, for example, a biocide, a pharmaceutical, a perfume or flavour, a fertilizer, or a plant hormone. For sustained release, the active substance is dispensed or distributed in a supporting material, so that it slowly dissolves or diffuses into the specified environment. Examples of such formulations are known, for example, from US Patent Application Publication No US 2009/0165515A1, European Patent Application No EP0218148A1 and U.S. Pat. No. 3,994,439.
Sustained-release formulations in medical applications can control rate and period of a drug delivery to a certain degree. It is known that traditional therapies with repeated drug administration result in a saw-tooth curve of drug concentration in the bloodstream. The sustained-release formulations enable keeping the drug concentration in a so-called “therapeutic window” for a prolonged time span. Polymers, such as PLGA (poly-(lactic-co-glycolic acid)) are common carriers for such sustained-release formulations, as described in “Polymeric Delivery Systems for Controlled Drug Release”, R. Langer, Chem. Eng. Commun 6 (1980) 1-3, 1. Several modifications of the sustained-release formulation were introduced in order to expand the timescale of the therapeutic window to several weeks or months by reducing diffusion of the active substances. Successful examples of such sustained-release formulations are intercalation of inert nanoparticles (as known from U.S. Pat. No. 6,821,928]) or microencapsulation of the AS (as known from U.S. Pat. No. 6,265,389).
A typical release pattern for slow-release systems is first-order kinetics, in which release rate of the active substance decreases exponentially with time, with relatively high initial release rate. High initial concentrations of some drugs in the bloodstream can cause toxic side effects. After a certain period of time, the concentration of the drug in the bloodstream falls below the necessary therapeutic level [see for a discussion “Nanostructure-mediated drug delivery”, G. A. Hughes, Nanomedicine: Nanotechnology, Biology, and Medicine 1 (2005) 22]. In contrast, with a zero-order kinetic release pattern for the active substance a substantially steady therapeutic level can be maintained over the treatment period. This is preferably done with only a single administration of the active substance.
The terms “zero-order release” and “zero-order kinetic” are to be understood in this context as a release pattern of the active substance from a substrate over time, in which the first temporal derivation of the release rate is substantially zero, or, in other words, the release rate remains substantially constant with time. Similarly, the term “first-order release” or “first-order kinetic” is to be understood as a release pattern over time, in which the first temporal derivation of the release rate has a substantially fixed, time-independent value.
In the field of sustained-release formulation, nanoporous materials have drawn much attention as the nanoporous materials are suitable as supporting “host” materials for specific active substances. The ordered nanoporous materials are mainly based on silicon oxide, and, to a lesser extent, on other metal oxides, and comprise a specific oxide with a regular arrangement of pores [see, for example, “Ordered mesoporous materials” U. Ciesla and F. Schueth, Microporous and Mesoporous Materials 27 (1999) 2-3, 131-149].
The term “nanoporous material” (or oxide, silica, etc.) used in this disclosure is to be understood as a porous material with pore diameters substantially between 1 and 100 nm.
The term “mesoporous material” used in this disclosure is to be understood as a nanoporous material with pore diameters substantially between 2 and 50 nm (see J. Rouquerol et al., “Recommendations for the characterization of porous solids (Technical Report)”, Pure & Appl. Chem 66 (1994) 8 1739-1758. doi:10.1351/pac199466081739).
The term “monodisperse” as used in this disclosure refers to a collection of particles that are substantially of the same size, shape and mass.
It is known that porous silica (SiO2) is a non-toxic, biocompatible material that can incorporate a high volume of active substances into its open pore system. [regarding the biocompatibility see, for example: “Unique Uptake of Acid-Prepared Mesoporous Spheres by Lung Epithelial and Mesothelioma Cells” S. Blumen et al., American Journal of Respiratory and Molecular Biology vol. 36 (2007), pp. 333-342]. A further advantage of this class of materials, and more particularly, mesoporous ordered silica, is its extreme versatility regarding the shapes and sizes of its pore systems. The pore system can be controlled during the synthesis, thus making various pore sizes and geometries available.
Various structures of the silica materials with different pore geometries are commonly classified by a three-letter code followed by a number. A list of available structures can be found, e.g. in U.S. Pat. No. 7,767,004 B2, Table 1. Additionally, various functional organic groups can be selectively introduced onto the outer and inner surfaces [see “Mesoporous Materials for Drug Delivery”, M. Vallet-Regi et al., Angew. Chem. Int. Ed. 46 (2007) 7548].
The sustained release formulations comprise at least two components, namely, the supporting or host material (sometimes called substrate), and the particular active substance. Different superstructures of the two components are therefore imaginable. One superstructure for the sustained release formulation with a zero order kinetic is a “coated pure drug bead”, which has a bead exhibiting a core-shell structure. The core is formed by the pure active substance, and the shell is formed by a second, supporting material.
The theoretical release behaviour of such core-shell structures is described in “Dimensionless presentation for drug release from a coated pure drug bead” S. M. Lu, Int. J. of Pharmaceutics 112 (1994), 105-116. It can be derived from this article that a zero-order kinetic sustained release from of a single bead can principally be achieved, if the following three preconditions are fulfilled:                The concentration of the active substance at the border of core to shell remains constant over a prolonged timespan.        The diffusivity of the active substance in the core is much higher than its diffusivity in the shell.        The concentration of the active substance in the surrounding medium of the particle remains zero or negligibly small (perfect sink).        
All three preconditions might be, in principal, fulfilled by use of the coated pure drug beads, i.e. the core-shell structure. However, the encapsulation of the pure drug (as the active substance) has disadvantages concerning, for instance, the mechanical stability of core-shell structures during processing. Therefore, a entirely non-collapsible, rigid porous network such as a nanoporous silicate as a supporting material is helpful or often even necessary as, for example, described in US Patent Application No. 2003/175347A1.
The reported results from the coated pure drug beads can be adopted to the more general case of an active substance incorporated into a rigid porous medium. In this latter case, the relevant parameters, for example, the concentration of active substance at the core-shell transition are only weakly altered if the core is highly porous, comprising interconnected channels and an isotropic diffusion behaviour (cubic crystal system), and completely filled with the active substance. Typical examples demonstrate that diffusion of low-molecular substances in the porous systems, and therefore, their elution into the environment are relatively fast and mostly completed within minutes, or, sometimes, hours. [see “Inclusion of ibuprofen in mesoporous templated silica: drug loading and release property”, C. Charnay et al., European Journal of Pharmaceutics and Biopharmaceutics vol. 57 (2004) 3, pp. 533-540].
In the case of poorly water-soluble active substances, to which belong a vast number of pharmaceutically important substances [see U.S. Pat. No. 6,576,264 B1], all three preconditions outlined above are fulfilled. If the porous core-shell particle is loaded with a poorly water-soluble active substance and brought into an open biological environment, the biological environment will act as a sink for released molecules of the active substance. A steady concentration of the active substance at the core/shell frontier of the particle for a prolonged time can therefore be assumed, since the porous structure will be filled with water from the biological environment. This water acts as a transport medium for the solubilised molecules of the active substance, and keeps the concentration of the active substance at the shell substantially constant. The shell itself must be designed in a way that the shell strongly hinders the diffusion of the active substance.
It would be advantageous to incorporate a large number of the supporting materials in a carrier material, for example, in a polymer extrudate, instead of the preparation of a single large porous particle. The use of the single large porous particle involves the danger of a huge and unwanted overdose of the active substance in case of breaking, and, therefore, of uncontrolled fast release from this single large porous particle. In contrast, in case of the breakage of the polymer extrudate containing a large number of small particles, only a small fraction of the particles would be destroyed, and the amount of the active substance released would be much smaller. For medical applications, the use of such an assemblage of particles is therefore preferable.
In other applications, for example, in crop science, a wide-area application of the small particles as individual reservoirs for the active substances is additionally advantageous in order to achieve a substantially constant concentration of the active substance (e.g. biocides) in time and space. This allows a reduction of the total amount of the active substance per area unit, since any unnecessary local overdose in area or time can be avoided. Other examples may comprise glues, coatings and lacquers, in which the particles releasing, for example, a biocide can be incorporated and prevent the particular composition from fouling.
To ensure that such desirable release kinetics from a single particle can be transferred to an assemblage of particles, the size distribution of the particles in the assemblage must be substantially monodisperse and show only a small standard deviation.
This requirement is shown, for example, in “Modelling of drug-release from poly-disperse microencapsulated spherical particles”, C. Sirotti et al., J. Microencapsulation, 19 (2002) 5, 603-614. It can be even more clearly visualized if for each particle of a batch a perfect zero order kinetic is assumed, i.e. a constant release of the active substance over time until the reservoir (core) is emptied, followed by a sudden and abrupt stop.
The amount of the active substance incorporated into the particle is directly proportional to the volume of the core of the particle, which is related to the cube of the particle radius. The amount of released active substance per unit time is related directly to the surface area of the particle, which is the square of the particle's radius multiplied by 4π. Thus, not only the standard deviation (SDV) of the size of the core-depot, but also the SDV of the amount of the active substance released per time is strongly affected by the SDV of the particle's diameter. For example, the volumes of the smallest particles (2 micrometers in diameter) and the biggest particles (2.5 micrometers in diameter) in a mixture (that corresponds in this case to 11.1% deviation from a mean particle size of 2.25 micrometers) differ almost by the factor of two. It is thus obvious, that a broad size distribution of the particles results in a huge, undesired distortion of the aimed zero-order kinetics. Hence, the particle size distribution has to be as sharp as possible.
The correlation, visualizing quantitatively the effect of a different SDV for assemblies of the particles, can be derived as follows (if a large core and a negligible thin shell is assumed, so that rcore≈rcore+rshell, where rcore is the radius of the core and rshell is the radius of the shell).
The amount of incorporated substance is assumed to be directly proportional to the available volume of the depot, hence the mass of incorporated AS ism=c14/3r3=c2r3  Eq. 1
The amount of the active substance released per time is proportional to the surface of one particle
                                          ⅆ            m                                ⅆ            t                          =                                            c              3                        ⁢            4            ⁢                                                  ⁢            π            ⁢                                                  ⁢                          r              2                                =                                    c              4                        ⁢                          r              2                                                          Eq        .                                  ⁢        2            
Separation and integration of Eq. 2 leads to∫dm=∫0tc4r2dt  Eq. 3m=c4r2t  Eq. 4
Combination with Eq. 1 results in
                                                        c              2                                      c              4                                ⁢          r                =                                            c              5                        ⁢            r                    =          t                                    Eq        .                                  ⁢        5            
The Eq. 5 shows the time at which the core depot of the particle is emptied. It is linearly related to the radius of the particle and dependent on the diffusion rate of the active substance through the shell, which correlates with constant c3 and, therefore, c4.
Since the standard deviation and its influence on the release properties is the most interesting, constants c2, c4 and c5 in this example are defined to be equal to 1.
The size distribution of the particles is given by the Gaussian distribution
                              P          ⁡                      (            r            )                          =                              1                          σ              ⁢                                                2                  ⁢                                                                          ⁢                  π                                                              ⁢                      exp            ⁡                          (                                                -                                      1                    2                                                  ⁢                                                      (                                                                  r                        -                        μ                                            σ                                        )                                    2                                            )                                                          Eq        .                                  ⁢        6            where r is the particle radius, μ is the mean radius, σ is the standard deviation.
The amount of the active substance released by all the particles per time is given by the sum, and, hence, by the integral of P(t), multiplied by the surface area of the particles.
                                                        ⅆ              m                                      ⅆ              t                                ⁢                      1            m                          =                                            ∫                              r                ⁡                                  (                  t                  )                                            ∞                        ⁢                                          c                4                            ⁢                              r                2                            ⁢                              1                                  σ                  ⁢                                                            2                      ⁢                                                                                          ⁢                      π                                                                                  ⁢                              exp                ⁡                                  (                                                            -                                              1                        2                                                              ⁢                                                                  (                                                                              r                            -                            μ                                                    σ                                                )                                            2                                                        )                                            ⁢                                                          ⁢                              ⅆ                r                                                                        ∫              0              ∞                        ⁢                                          c                2                            ⁢                              r                3                            ⁢                                                          ⁢                              1                                  σ                  ⁢                                                            2                      ⁢                                                                                          ⁢                      π                                                                                  ⁢                              exp                ⁡                                  (                                                            -                                              1                        2                                                              ⁢                                                                  (                                                                              r                            -                            μ                                                    σ                                                )                                            2                                                        )                                            ⁢                              ⅆ                r                                                                        Eq        .                                  ⁢        7            
The denominator reflects the overall amount of the active substance, to normalize the curves obtained for different standard deviations and mean particle sizes. To calculate the release rate at a given time, the starting point of the integral of the nominator has first to be found from Eq. 5. The result is a value for a radius, corresponding to the sizes of the particles that no longer contain the active substance at a time t. Hence, the integration is done for all the particles that still contain active substance. The amount of the particles inside a given dr is multiplied by c4 r2, which gives the release rate (Eq. 2).
FIG. 16 shows four different curves relating to four different standard deviations. It can be clearly seen, that a relatively large SDV leads to a distorted release curve, in comparison to an almost rectangular curve for SDVs that are smaller than 10% of the mean particle size.